Effects of sertindole on sleep-wake states, electroencephalogram, behavioral patterns, and epileptic activity of rats

Abstract

COENEN, A. M. L., N. ATES, T. SRARSFELDT AND E. L. J. M. VAN LUIJTELAAR. Effects of sertittdole onsleep-wake states, electroencephalogram. behavioral potterns, and epileptic activity of rats. P HARMACOL BIOCHEM BEHAV 51(2/3) 353-357, 199X-In this study we addressed the effects of the S-HT, receptor antagonist sertindole in rats.The compound was administered in doses of 0.08. 0.32, and 1.28 mg/kg, whereas a control group received the solvent. The effects of sertindole on sleep-wake states, behavioral patterns, and background electroencephalogram were studied. Following injection of drug or solvent, we recorded the electroencephalogram and electromyogram for two periods of 4 h in the dark period of the light-dark cycle on 2 successive days. On the 1st day sertindole induced a significant increase in deep slow-wave sleep, but only with a dose of 0.32 mg/kg. Furthermore, a decrease in REM sleep in alI three drug groups was established. The suppression of REM sleep was still present on the 2nd day. Sertindole also induced a decrease in alternation between behavioral patterns on the 1st day. There were no significant changes in the spectral content of the background eleetroencephalogram. In a parallel experiment it appeared that sertindole had no main effects on epileptic spike-wave discharges. This was established with a dose of 1.28 mg/kg sertindole in rats with absence seizures. These Endings suggest that sertindole. similar to other compounds modulating 5-HT, receptors, influences sleep-wake states in rats by decreasing REM sleep and mildly increasing deep slow-wave sleep, whereas behavioral variation is slightly diminished, with no effects on the background EEG and almost no effects on spike-wave discharges. (15). It has been shown in rats that compounds which particularly modulate the 5-HT2 receptor influence sleep-wake states. For example, 5.HT, antagonists such as mianserin and ritanserin increase deep slow-wave sleep, which is accompanied by a decrease of REM sleep (1 l-13). A decrease of REM sleep was not found for RP 62203, a newer 5.HT, antagonist, which also enhanced deep slow-wave sleep (28). In accordance with this it was noted that the administration of selective 5-HT uptake inhibitors gives rise to increased waking (32).A new drug with promising biologic effects is sertindole, a powerful 5-HTz receptor antagonist (25). The question put forward in this experiment was whether sertindole also has effects on sleep-wake states and furthermore, on behavioral parameters, because it is preferable that putative hypnotics should only promote sleep without affecting behavioral patterns. Also, the effects of sertindole on the spectral content of the background electroencephalogram (EEG) were established. Classification of drugs according to their pharmacologic EEG fingerprint is increasingly important (8,20,36).Because it is known that drugs influencing sleep-wake states may also affect epileptic discharges, the putative epilepsy-modulating properties of sertindole were evaluated in a parallel experiment. This w...

Sertindole: EEG Analysis, Tolerability, and Clinical Efficacy

“…However, there was no significant slowing of the background electroencephalogram after sertindole administration. Additionally, sertindole was not found to have any effects on epileptic spike-wave discharges [7]. Thus, the previous study in rats as well as ours in patients with schizophrenia support the conclusion that in comparison to the majority of other antipsychotics, sertindole has a low propensity to increase SWA and epileptiform discharges in EEG.…”

“…To our best knowledge, this study is the first to report EEG changes during sertindole treatment in patients with schizophrenia. We found only 1 previous study in the literature that investigated effects of sertindole on sleep-wake states, behavioral changes, EEG recordings, and epileptic activity in rats [7]. It showed that sertindole mildly increases slow wave sleep and suppresses REM sleep in relation to its antagonistic activity at serotonergic 5-HT2 receptors.…”

“…Common adverse effects (1-10 % incidence) include sedation, weight gain, orthostatic hypertension, changes in urinalysis, ejaculation disorder, and erectile dysfunction [6]. There is, however, not much scientific information on the influence of sertindole on brain bioelectrical activity (EEG) besides 3 studies in rat models [7][8][9], 1 case report [10], and our previous publication in a small group of 19 patients [11].…”